WO1998010795B1 - Tumor homing molecules, conjugates derived therefrom, and methods of using same - Google Patents

Abstract

The present invention provides tumor homing molecules, which selectively home to a tumor. The invention also provides methods of using a tumor homing molecule to target an agent such as a drug to a selected tumor or to identify the target molecule expressed by the tumor. The invention also provides methods of targeting a tumor containing angiogenic vasculature by contacting the tumor with a molecule that specifically binds an αv-containing integrin. The invention further provides molecules that can selectively home to angiogenic vasculature. In addition, the invention provides a target molecule, which is specifically bound by a tumor homing molecule and is expressed by angiogenic vasculature. The invention also provides antibodies that bind to the target molecule and peptidomimetics that competitively inhibit binding of a ligand to the target molecule.

Claims

AMENDED CLAIMS

[received by the International Bureau on 15 May 1998 (15.05.98); original claim 35 amended; new claims 73-78 added; remaining claims unchanged (2 pages)]

35. A tumor homing peptide selected from the group consisting of CLSGSLSC (SEQ ID NO: 4) and CGSLVRC

(SEQ ID NO: 5) .

36. A tumor homing molecule identified by in vivo panning, comprising the steps of:

a) administering to a first subject having a tumor a library of diverse molecules;

b) collecting a sample of the tumor;

c) identifying a molecule that homes to said tumor;

d) collecting a sample of normal tissue corresponding to said tumor; and

e) determining that said molecule that homes to said tumor is not present in said normal tissue, thereby identifying said molecule as a tumor homing molecule,

provided said molecule is not an antibody.

37. A method of directing a moiety to a tumor, comprising contacting the tumor with the conjugate of claim 1.

38. The method of claim 37, wherein said contacting step is performed in vi tro .

39. The method of claim 37, wherein said contacting step is performed in vivo.

72. The method of claim 69, wherein said molecule is CDCRGDCFC (SEQ ID NO: 14) .

73. A tumor homing peptide selected from the group consisting of CNGRC (SEQ ID NO : 8) and

CNGRCVSGCAGRC (SEQ ID NO: 3) .

74. The conjugate of claim 1, wherein said moiety induces apoptosis in a cell.

75. A tumor homing peptide, comprising the amino acid sequence GSL.

76. A target molecule, which is expressed in tumor vasculature, wherein said target molecule binds a tumor homing peptide comprising the amino acid sequence GSL.

77. A target molecule, which is expressed in angiogenic vasculature, wherein said target molecule binds a tumor homing peptide comprising the amino acid sequence GSL.

78. A target molecule, which is expressed in angiogenic vasculature, wherein said target molecule binds a tumor homing peptide comprising the amino acid sequence NGR.

STATEMENT UNDER ARTICLE 19

Upon entry of the amendments, claims 1 to 78 will be pending. The amendments shown above and included on the Substitute pages are supported for the following reasons.

The specification has been amended at page 34, lines 9-10, to correctly indicate that the size of a phage is 900-1000 nm. Support for the amendment is provided, in part, by the language at page 34, as well as by knowledge in the art regarding the size of M13 bacteriophage, which harbor the fuse 5 vector (-see page 70, lines 11-13; and Exhibit A, Pasqualini et al . , Nature Biotechnol. 15:542 (1997), at page 545, right column second paragraph, indicating phage are 900 nm in length) . Thus, the amendment merely corrects an omission in not deleting a question posed prior to filing the specification and is supported, in part, by the specification and by knowledge in the art and, therefore, does not add new matter. Entry of Substitute page 34, containing the amended language, therefore, respectfully is requested.

Claim 35 has been amended to cancel recitation of the peptide of SEQ ID NO: 3, which has been added to new claim 73, and to insert therefor the peptide of SEQ ID NO: 4, which is supported in Table 2 (page 80, line 14) . The amendment is made to include only peptides sharing a "GSL" motif in claim 35 and, similarly, to include only peptides having a "CNGRC" motif in new claim 73. Thus, new claim 73 recites the peptide of SEQ ID NO: 3 and the peptide, CNGRC (SEQ ID NO: 8) . New claim 73, including the CNGRC peptide, is supported, for example, at page 38, line 35, to page 39, line 2, which indicates that CNGRC is a tumor homing peptide. Thus, the amendment to claim 35 and new claim 73 are supported by the specification and the claims as filed and do not add new matter.

New claim 74 also has been added. New claim 74 is supported, for example, at page 45, lines 14-19, and, therefore, does not add new matter. New claim 75 is supported, for example, at page 4, lines 13-19; at page 38, lines 6-33; and at page 40, lines 27-35, which indicate that "GSL" containing peptides are considered within the claimed invention, and, therefore, the new claims do not add new matter .

New claims 76 to 78 are based, in part, on originally filed claim 52 and are supported, for example, at page 67, line 34, to page 68, line 17, and, for example, at page 4, lines 13-19, and page 5, lines 13-16. Thus, new claims 76 to 78 do not add new matter.

For the above reasons, it is submitted that the amendments to the claims and the new claims do not add new matter. Accordingly, entry of Substitute pages 95 and 100, containing the amended claim 35 and new claims 73 to 78, respectfully is requested.

Entry of Substitute pages--35, 95 and 100 respectfully is requested. The Examiner is invited to contact the undersigned attorney or Cathryn Campbell if there are any questions relating to the subject application.